Method for constructing full-alkyl quaternary carbon stereo center by stereospecific conversion of chiral tertiary alcohol

Abstract

The invention relates to the field of chemical synthesis, and discloses a method for constructing a full-alkyl quaternary carbon stereocenter through stereospecific conversion of chiral tertiary alcohol. The method successfully solves the industrial problem that the peralkyl quaternary carbon center is difficult to construct with high stereoselectivity due to huge steric hindrance and lack of electron difference, the process shows excellent stereospecificity and chemical selectivity, the ee value of the product is as high as 98%, the dr value is superior to 20: 1, and meanwhile, the excellent yield of 90% or above is kept; besides, according to the scheme, the substrate is wide in universality and can be compatible with various chemical small molecule substrates of different structures, the used reagents such as triethyl aluminum and KHMDS are cheap and easy to obtain, operation is easy and convenient, and a simple and efficient stereospecific conversion strategy with industrial application potential is provided for synthesis of complex drug intermediates.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically discloses a method for constructing an all-alkyl quaternary carbon stereocenter through the stereospecific transformation of chiral tertiary alcohols. Background Technology

[0002] Full-carbon and quaternary-carbon steric centers are widely found in many biologically important natural products and drug molecules. For example, paclitaxel, Hainan torreya lactone, and gibberellin all contain one or more full-carbon and quaternary-carbon chiral centers in their molecular skeletons. These structural units play a decisive role in the biological activity and selectivity of the molecules. However, due to significant steric repulsion and differences between substituents, efficiently catalyzing the construction of such sterically crowded and structurally diverse steric centers remains a long-standing challenge in synthetic chemistry. Although strategies such as organocatalysis and transition metal catalysis have made many breakthroughs in the construction of full-carbon and quaternary-carbon chiral centers, efficient methods for constructing full-alkyl quaternary-carbon steric centers are still very limited.

[0003] Chiral tertiary alcohols, as important building blocks in synthesis, have shown significant advantages in constructing quaternary carbon stereocenters. They can construct quaternary carbon stereocenters through stereospecific transformations, achieving nucleophilic substitution reactions of heteroatoms or C atoms at specific positions, but they cannot construct universal all-alkyl quaternary carbon stereocenters.

[0004] Therefore, developing a method for constructing all-alkyl quaternary carbon stereocenters is of great significance in organic synthesis. Summary of the Invention

[0005] To address the problems existing in the prior art, the first aspect of this invention proposes a compound D, such as: ; The R 1 Selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted alkoxy, -OR a The R a Selected from hydrogen and hydroxyl protecting groups; The R 2 and R 3 Each is independently selected from substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, and hydroxyl groups; The R 4 Selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl; The R 5 Selected from hydrogen, -C(O)OR b The R b Selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl; The n is selected from any positive integer from 1 to 5; The atoms marked with * are each independently of the R configuration, S configuration, or non-chiral carbon atom.

[0006] In some embodiments of compound D, the R a Selected from any one of tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, methanesulfonyl, trifluoromethanesulfonyl, and p-nitrobenzenesulfonyl; and / or, the R b It is selected from any one of methyl, ethyl, and isopropyl.

[0007] In some embodiments of compound D, the R 1 and R 2 Each is independently selected from any one of benzyloxy, methoxy, ethoxy, methyl, ethyl, or isopropyl.

[0008] A second aspect of the present invention provides a compound, which is any one of d1 to d5 as follows: .

[0009] A third aspect of this invention provides a method for preparing a chiral all-alkyl quaternary carbon stereocenter compound D, comprising: Compound C, a first organic solvent, and triethylaluminum were mixed and reacted under an inert gas atmosphere to give compound D. ; The atoms, n, and R marked with * 1 R 2 R 3 R 4 R 5 As defined in any of the first aspects.

[0010] In some embodiments of the preparation method of compound A, the molar amount of compound B added to each 1L of the first organic solvent is 100~220mmol.

[0011] In some embodiments of the preparation method of compound A, the molar amount of triethylaluminum added to each 1L of the first organic solvent is 150~350mmol.

[0012] A fourth aspect of this invention provides a method for preparing compound C, comprising: Compound B, o-fluoropyridine compound e, and a second organic solvent were mixed and reacted with potassium bis(trimethylsilyl)amino to give compound C under an inert gas atmosphere. ; The atoms, n, and R marked with * 1 R 2 R 3 R4 R 5 As defined in any of the first aspects.

[0013] In some embodiments of the preparation method of compound C, the molar amount of compound B added to each 1L of the second organic solvent is 150~240mmol.

[0014] In some embodiments of the preparation method of compound C, the molar amount of o-fluoropyridine compound e added to each 1L of the second organic solvent is 180~300mmol.

[0015] In some embodiments of the preparation method of compound C, the molar amount of bis(trimethylsilyl)aminopotassium added to each 1L of the second organic solvent is 120~270mmol; and / or, the reaction occurs at -5~5°C.

[0016] The fifth aspect of this invention provides a compound, which is any one of c1 to c5 as follows: .

[0017] The sixth aspect of this invention provides a compound, of any one of the following b1 to b5: .

[0018] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), and n-propyl ( n -Pr, -CH2CH2CH3), isopropyl ( i -Pr, -CH(CH3)2), n-butyl ( n -Bu、-CH2CH2CH2CH3), isobutyl ( i -Bu、-CH2CH(CH3)2), sec-butyl( s -Bu、-CH(CH3)CH2CH3), tert-butyl( t-Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH (CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl ( -CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0019] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group contains 1-3 carbon atoms; and in still another embodiment, the alkylene group contains 1-2 carbon atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), etc.

[0020] Advantages of this invention: This invention provides a novel method for constructing fully alkyl quaternary carbon stereocenters. Through efficient coupling and subsequent transformation of chiral tertiary alcohols with o-fluoropyridine compounds, it successfully solves the industry challenge of constructing fully alkyl quaternary carbon centers with high stereoselectivity due to significant steric hindrance and lack of electronic differentiation. This process exhibits excellent stereospecificity and chemoselectivity, with an ee value as high as 98% and a dr value better than 20:1, while maintaining an excellent yield of over 90%. In addition, this method has broad substrate universality, compatible with a variety of small chemical molecules with different structures, and the reagents used, such as triethylaluminum and KHMDS, are inexpensive and readily available. The operation is simple. The core of the synthesized compound lies in the successful construction of a fully alkyl quaternary carbon stereocenter. This structural unit is widely present in natural products with important biological activities and is a key framework determining the spatial conformation and biological activity of drug molecules. It not only provides highly precise stereodirection for drug molecules, significantly enhancing drug selectivity and efficacy, but this fully alkyl-substituted quaternary carbon structure also has good chemical and metabolic stability, effectively resisting enzyme degradation in vivo and prolonging the metabolic half-life of drugs in vivo. Furthermore, the method achieves an ee value of 98%, ensuring the high purity of the active drug isomer. This has significant development value for reducing drug toxicity and improving the safety of clinical drug use. The method provides a simple, efficient, and industrially applicable stereospecific conversion strategy for the synthesis of complex drug intermediates. Attached Figure Description

[0021] Figure 1 The hydrogen NMR spectrum of the sample obtained in Example 1 of this invention; Figure 2 The carbon NMR spectrum of the sample obtained in Example 1 of this invention; Figure 3 The boron NMR spectrum of the sample obtained in Example 2 of this invention; Figure 4 The 1H NMR spectrum of the sample obtained in Example 2 of this invention; Figure 5 The carbon NMR spectrum of the sample obtained in Example 3 of this invention; Figure 6 The boron NMR spectrum of the sample obtained in Example 3 of this invention; Figure 7 The hydrogen NMR spectrum of the sample obtained in Example 4 of this invention; Figure 8 The carbon NMR spectrum of the sample obtained in Example 4 of this invention; Figure 9 The boron NMR spectrum of the sample obtained in Example 5 of this invention; Figure 10 This is the 1H NMR spectrum of the sample obtained in Example 5 of the present invention. Detailed Implementation

[0022] The technical solutions of the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0023] Example 1

[0024] Under nitrogen protection, a tetrahydrofuran solution (5 mL) of cuprous chloride (0.5 mmol, 0.1 equiv.) was cooled to 0 °C and stirred for 0.5 h. Grignard reagent f1 (6 mmol, 1.2 equiv.) was then slowly added, followed by epoxide a1 (5 mmol, 1.0 equiv.). The reaction temperature was raised to room temperature, and stirring continued for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound b1.

[0025]

[0026] Under nitrogen protection, a tetrahydrofuran solution (10 mL) of chiral tertiary alcohol b1 (2 mmol, 1.0 equiv.) and o-fluoropyridine compound e (1.2 equiv.) was cooled to 0 °C, followed by the addition of a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (1 M, 1.1 equiv., 2.2 mL), and stirring was continued at 0 °C for 6 hours. The reaction was quenched with saturated ammonium chloride solution, the mixture was heated to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound c1.

[0027] Under nitrogen protection, a 3.3 mL solution of compound c1 (0.5 mmol, 1.0 equiv.) in dichloromethane was cooled to -78 °C, followed by the slow addition of a 1 mL solution of triethylaluminum in dichloromethane (2 M, 4.0 equiv.). The mixture was stirred at -40 °C for 24 hours. The reaction was quenched by the slow addition of saturated sodium potassium tartrate solution. Once no gas was generated, the mixture was moved to room temperature and stirred for 12 hours. Ethyl acetate was added for extraction, the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound d1 in 92% yield with an ee value of 96%. The 1H and 1C spectra of d1 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.31-7.27 (m, 2H), 7.21-7.15 (m, 3H), 3.41(t, J = 6.6 Hz, 2H), 3.36 (s, 3H), 2.54-2.49 (m, 2H), 1.60-1.55 (m, 2H), 1.52-1.47 (m, 2H), 1.35-1.26 (m, 6H), 0.90 (s, 3H), 0.85 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 143.79, 128.42, 125.62, 73.03, 58.68,41.43, 38.86, 35.31, 31.52, 30.71, 30.40, 24.57, 20.28, 8.11. Example 2

[0028] Under nitrogen protection, a tetrahydrofuran solution (5 mL) of cuprous chloride (0.5 mmol, 0.1 equiv.) was cooled to 0 °C and stirred for 0.5 h. Grignard reagent f1 (6 mmol, 1.2 equiv.) was then slowly added, followed by epoxide a2 (5 mmol, 1.0 equiv.). The reaction temperature was raised to room temperature, and stirring continued for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound b2.

[0029] Under nitrogen protection, a tetrahydrofuran solution (10 mL) of chiral tertiary alcohol b2 (2 mmol, 1.0 equiv.) and o-fluoropyridine compound e (1.2 equiv.) was cooled to 0 °C, followed by the addition of a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (1 M, 1.1 equiv., 2.2 mL), and stirring was continued at 0 °C for 6 hours. The reaction was quenched with saturated ammonium chloride solution, the mixture was heated to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound c2.

[0030] Under nitrogen protection, a 3.3 mL solution of compound c2 (0.5 mmol, 1.0 equiv.) in dichloromethane was cooled to -78 °C, followed by the slow addition of a 1 mL solution of triethylaluminum in dichloromethane (2 M, 4.0 equiv.). The mixture was stirred at -40 °C for 24 hours. The reaction was quenched by the slow addition of saturated sodium potassium tartrate solution. Once no gas was generated, the mixture was moved to room temperature and stirred for 12 hours. Ethyl acetate was added for extraction, the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound d2 in 91% yield with an ee value of 98%. The 1H and 1C spectra of d2 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 2H), 7.23 (d, J = 7.8Hz, 2H), 3.89 (s, 3H), 3.38 (t, J = 6.5 Hz, 2H), 3.33 (s, 3H), 2.57-2.44 (m,2H), 1.55 (p, J = 6.8 Hz, 2H), 1.49-1.43 (m, 2H), 1.32-1.22 (m, 6H), 0.87 (s,3H), 0.81 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 167.26, 149.39, 129.79, 128.46, 128.44,127.64, 72.93, 58.65, 52.02, 41.01, 38.77, 35.35, 31.44, 30.66, 30.53, 24.51,20.25, 8.08. Example 3

[0031] Under nitrogen protection, a tetrahydrofuran solution (5 mL) of cuprous chloride (0.5 mmol, 0.1 equiv.) was cooled to 0 °C and stirred for 0.5 h. Grignard reagent f3 (6 mmol, 1.2 equiv.) was then slowly added, followed by epoxide a3 (5 mmol, 1.0 equiv.). The reaction temperature was raised to room temperature, and stirring continued for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound b3.

[0032] Under nitrogen protection, a tetrahydrofuran solution (10 mL) of chiral tertiary alcohol b3 (2 mmol, 1.0 equiv.) and o-fluoropyridine compound e (1.2 equiv.) was cooled to 0 °C, followed by the addition of a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (1 M, 1.1 equiv., 2.2 mL), and the mixture was stirred at 0 °C for 6 hours. The reaction was quenched with saturated ammonium chloride solution, the mixture was heated to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound c3.

[0033] Under nitrogen protection, a 3.3 mL solution of compound c3 (0.5 mmol, 1.0 equiv.) in dichloromethane was cooled to -78 °C, followed by the slow addition of a 1 mL solution of triethylaluminum in dichloromethane (2 M, 4.0 equiv.). The mixture was stirred at -40 °C for 24 hours. The reaction was quenched by the slow addition of saturated sodium potassium tartrate solution. Once no gas was generated, the mixture was moved to room temperature and stirred for 12 hours. Ethyl acetate was added for extraction, the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound d3 in 90% yield (dr > 20:1). The 1H and 1C NMR spectra of d3 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.38-7.35 (m, 4H), 7.33-7.27 (m, 3H), 7.21-7.19 (m, 3H), 4.54 (d, J= 2.7 Hz, 2H), 3.40-3.37 (m, 1H), 3.32-3.30 (m, 1H), 2.57-2.48 (m, 2H), 1.77-1.72 (m, 1H), 1.54-1.47 (m, 2H), 1.46-1.41 (m, 1H),1.37-1.29 (m, 3H), 1.27-1.22 (m, 1H), 1.11 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H),0.91 (s, 3H), 0.86 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 143.81, 138.95, 128.44, 127.67, 127.53,125.62, 76.05, 73.11, 41.41, 35.90, 35.21, 34.35, 31.55, 30.42, 27.37, 24.62,17.47, 8.12. Example 4

[0034] Under nitrogen protection, a tetrahydrofuran solution (5 mL) of cuprous chloride (0.5 mmol, 0.1 equiv.) was cooled to 0 °C and stirred for 0.5 h. Grignard reagent f4 (6 mmol, 1.2 equiv.) was then slowly added, followed by epoxide a4 (5 mmol, 1.0 equiv.). The reaction temperature was raised to room temperature, and stirring continued for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound b4.

[0035]

[0036] Under nitrogen protection, a tetrahydrofuran solution (10 mL) of chiral tertiary alcohol b4 (2 mmol, 1.0 equiv.) and o-fluoropyridine compound e (1.2 equiv.) was cooled to 0 °C, followed by the addition of a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (1 M, 1.1 equiv., 2.2 mL), and the mixture was stirred at 0 °C for 6 hours. The reaction was quenched with saturated ammonium chloride solution, the mixture was heated to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound c4.

[0037] Under nitrogen protection, a 3.3 mL solution of compound c4 (0.5 mmol, 1.0 equiv.) in dichloromethane was cooled to -78 °C, followed by the slow addition of a 1 mL solution of triethylaluminum in dichloromethane (2 M, 4.0 equiv.). The mixture was stirred at -40 °C for 24 hours. The reaction was quenched by the slow addition of saturated sodium potassium tartrate solution. Once no gas was generated, the mixture was moved to room temperature and stirred for 12 hours. Ethyl acetate was added for extraction, the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound d4 in 47% yield (dr > 20:1). The 1H and 1C NMR spectra of d4 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.20-7.15 (m, 3H), 3.92-3.90 (m, 1H),3.87-3.84 (m, 1H), 2.48-2.43 (m, 2H), 2.43 (s, 3H), 1.77-1.67 (m, J = 6.7 Hz,1H), 1.45-1.39 (m, 2H), 1.30-1.23 (m, 3H), 1.21-1.18 (m, 1H), 1.13-1.08 (m,1H), 1.07-0.99 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.83 (s, 3H), 0.80 (t, J =7.5 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 144.75, 143.54, 133.25, 129.91, 128.45,128.38, 128.01, 125.69, 75.13, 41.25, 35.64, 35.12, 33.70, 31.34, 30.33,26.58, 24.45, 21.72, 16.68, 8.04. Example 5

[0038] Under nitrogen protection, a tetrahydrofuran solution (5 mL) of cuprous chloride (0.5 mmol, 0.1 equiv.) was cooled to 0 °C and stirred for 0.5 h. Grignard reagent f5 (6 mmol, 1.2 equiv.) was then slowly added, followed by epoxide a5 (5 mmol, 1.0 equiv.). The reaction temperature was raised to room temperature, and stirring continued for 12 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound b5.

[0039]

[0040] Under nitrogen protection, a tetrahydrofuran solution (10 mL) of chiral tertiary alcohol b5 (2 mmol, 1.0 equiv.) and o-fluoropyridine compound e (1.2 equiv.) was cooled to 0 °C, followed by the addition of a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (1 M, 1.1 equiv., 2.2 mL), and the mixture was stirred at 0 °C for 6 hours. The reaction was quenched with saturated ammonium chloride solution, the mixture was heated to room temperature, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give compound c5.

[0041] Under nitrogen protection, a 3.3 mL solution of compound c5 (0.5 mmol, 1.0 equiv.) in dichloromethane was cooled to -78 °C, followed by the slow addition of a 1 mL solution of triethylaluminum in dichloromethane (2 M, 4.0 equiv.). The mixture was stirred at -40 °C for 24 hours. The reaction was quenched by the slow addition of saturated sodium potassium tartrate solution. Once no gas was generated, the mixture was moved to room temperature and stirred for 12 hours. Ethyl acetate was added for extraction, the organic phases were combined, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give compound d5 in 90% yield (dr > 20:1). The 1H and 1C NMR spectra of d5 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.33-7.31 (m, 3H), 7.23-7.20 (m, 2H), 2.60-2.50 (m, 2H), 1.56-1.48 (m, 2H), 1.44-1.40 (m, 1H), 1.38-1.27 (m, 5H), 1.27-1.16 (m, 2H), 1.10-1.07 (m, 1H), 0.94-0.92 (m, 9H), 0.88 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 143.91, 128.45, 125.63, 41.50, 36.09,35.43, 35.21, 31.64, 30.47, 30.23, 29.67, 24.67, 19.56, 11.63, 8.14.

Claims

1. A compound D, such as: ； The R 1 Selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted alkoxy, -OR a The R a Selected from hydrogen and hydroxyl protecting groups; The R 2 and R 3 Each is independently selected from substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl, and hydroxyl groups; The R 4 Selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl; The R 5 Selected from hydrogen, -C(O)OR b The R b Selected from hydrogen, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched alkyl; The n is selected from any positive integer from 1 to 5; The atoms marked with * are each independently of the R configuration, S configuration, or non-chiral carbon atom.

2. The compound D according to claim 1, characterized in that, The R a Selected from any one of tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, methanesulfonyl, trifluoromethanesulfonyl, and p-nitrobenzenesulfonyl; and / or, the R b It is selected from any one of methyl, ethyl, and isopropyl.

3. The compound D according to claim 1, characterized in that, The R 1 R 2 R 3 R 4 Each is independently selected from any one of benzyloxy, methoxy, ethoxy, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, or tert-butyl.

4. A compound, of any one of the following d1 to d5: 。 5. A method for preparing a chiral all-alkyl quaternary carbon stereocenter compound D, comprising: Compound C, a first organic solvent, and triethylaluminum were mixed and reacted under an inert gas atmosphere to give compound D. ； The atom, n, and R marked with * 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1 to 3.

6. The method for preparing compound D according to claim 4, characterized in that, The amount of compound C added in each 1L of the first organic solvent is 100~220 mmol; and / or, the amount of triethylaluminum added in each 1L of the first organic solvent is 150~350 mmol; and / or, the first organic solvent is selected from any one or a mixture of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, and toluene.

7. A method for preparing compound C, comprising: Compound B, o-fluoropyridine compound e, and a second organic solvent were mixed and reacted with potassium bis(trimethylsilyl)amino to give compound C under an inert gas atmosphere. ； The atom, n, and R marked with * 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1 to 3.

8. The method for preparing compound C according to claim 6, characterized in that, The amount of compound B added to each 1L of the second organic solvent is 150-240 mmol; and / or, the amount of o-fluoropyridine compound e added to each 1L of the second organic solvent is 180-300 mmol; and / or, the second organic solvent is selected from any one or a mixture of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, and toluene; and / or, the amount of bis(trimethylsilyl)aminopotassium added to each 1L of the second organic solvent is 120-270 mmol; and / or, the reaction occurs at -5 to 5°C.

9. A compound, having any of the following c1 to c5 values: 。 10. A compound, as described in any of the following b1 to b5: 。

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